The Hajos-Parrish-Eder-Sauer-Wiechert reaction can be considered as the origin of asymmetric organocatalysis, giving rise to the Wieland-Miescher ketone 1 (WMK), a versatile building block. Although 40 years have passed since its discovery, a highly enantioselective and scalable synthesis of the WMK has remained elusive. This account details a solution to that problem that came about in the development of methodology towards C-8a WMK analogues as part of the total synthesis of complex diterpene natural products. The work has been placed in the context of the historical background and reactivity of this important building block, highlighting the challenges faced by organocatalysis in large-scale reactions.
The first total synthesis of anominine has been achieved, and the absolute configuration of the product has been determined. The key features include the development of a new, highly efficient organocatalyzed method for the asymmetric synthesis of Wieland-Miescher ketone building blocks, an unusual selenoxide [2,3]-sigmatropic rearrangement, and a ZrCl(4)-catalyzed indole coupling as well as several chemoselective transformations controlled by the structurally congested nature of the bicyclic core.
A concise synthesis of the Lycopodium alkaloid lycoposerramine Z is reported. Key to the strategy is a one-pot organocatalyzed Michael reaction followed by a domino Robinson annulation/intramolecular aza-Michael reaction promoted by LiOH, leading to enantiopure cis-decahydroquinolines.
An unprecedented C-C coupling reaction between alkenes and ketones by hydrogen-atom transfer, using Fe(acac) and PhSiH in EtOH, is described. This mild protocol features high site selectivity and allows the construction of sterically congested structures containing tertiary alcohols and quaternary centers. The overall process introduces a novel strategic bond disconnection for ring-closing reactions.
A highly efficient (93% overall yield) and enantioselective (94% ee) synthesis of the WielandMiescher ketone (10-g scale) through a solvent-free Robinson annulation procedure is reported. The process involves only 1 mol% triethylamine as the base in the initial Michael process and the organocatalyst N-tosyl-(S a )-binam-l-prolinamide (2 mol%) and benzoic acid (0.5 mol%) for the intramolecular aldol process. This green protocol is applied to a wide range of valuable building block analogues of the Wieland-Miescher ketone (10 examples). Among these, a noteworthy compound for terpene synthesis is the 8a-allyl derivative, which is prepared in 93% yield and 97% ee in a process allowing the recovery and reutilization of the organocatalyst. Furthermore, a one-pot, two-step process has also been developed.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.